Parkinson's Disease (PD) is characterized by the loss of dopaminergic (DA) neurons. Only 5-10% of PD cases have a direct genetic origin; however, exposure to herbicides, pesticides, and interaction with the soil are all potential risk factors. A soil bacterium, Streptomyces venezuelae (S. ven), produces a secondary metabolite that causes age- and dose- dependent DA neurodegeneration in C. elegans. Studies from our lab determined that exposure to the S. ven metabolite causes oxidative stress, mitochondrial fragmentation and enhanced reactive oxygen species (ROS). Upon metabolite exposure, significantly more
daf-16 accumulates within nuclei. Recently, we discovered that exposure to the S. ven metabolite is associated with hormetic effects. Specifically, at high concentrations of metabolite (20X), we observe dopaminergic neurodegeneration and enhanced ROS in N2 animals, whereas at low concentrations (5X), the neurons did not display neurodegeneration. We then extended these observations to lifespan studies in N2 animals. Notably, the higher concentration (20X) decreased lifespan in wild-type animals whereas the 5X concentration extended lifespan.
daf-16 mutants were then examined with both concentrations of metabolite in lifespan assays. Notably,
daf-16 mutants displayed no significant differences between solvent and metabolite at both high and low concentrations, suggesting the hormetic response is
daf-16 dependent. Considering
daf-16 is the primary transcription factor of several key aging pathways, we investigated the impact of S. ven metabolite on the aging process of C. elegans mutants in the insulin signaling pathway. When both
daf-2 and
age-1 mutants were exposed to the 5X concentration of S. ven, there was no significance difference between treatments. Yet, when
daf-18 mutants were exposed to the same concentration, lifespan extension remained. These data suggest that the insulin signaling pathway is impacted following chronic metabolite exposure. Additionally, when exposed to the 20X concentration of S. ven metabolite,
aak-2 mutants displayed no significant difference between solvent and metabolite. However, when
aak-2 mutants were exposed to the metabolite at the 5X concentration, mutants displayed a decreased lifespan. Taken together, these data indicate that functional
aak-2 might be important for increased lifespan when combating toxicants following chronic exposure.